Vitamin D Receptor Antagonist MeTC7 Inhibits PD-L1
Small-molecule inhibitors of PD-L1 are postulated to control immune evasion in tumors similar to antibodies that target the PD-L1/PD-1 immune checkpoint axis. However, the identity of targetable PD-L1 inducers is required to develop small-molecule PD-L1 inhibitors. In this study, using chromatin imm...
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| Veröffentlicht in: | Cancers 2023-06, Vol.15 (13), p.3432 |
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| creator | Khazan, Negar Quarato, Emily R Singh, Niloy A Snyder, Cameron W A Moore, Taylor Miller, John P Yasui, Masato Teramoto, Yuki Goto, Takuro Reshi, Sabeeha Hong, Jennifer Zhang, Naixin Pandey, Diya Srivastava, Priyanka Morell, Alexandra Kawano, Hiroki Kawano, Yuko Conley, Thomas Sahasrabudhe, Deepak M Yano, Naohiro Miyamoto, Hiroshi Aljitawi, Omar Liesveld, Jane Becker, Michael W Calvi, Laura M Zhovmer, Alexander S Tabdanov, Erdem D Dokholyan, Nikolay V Linehan, David C Hansen, Jeanne N Gerber, Scott A Sharon, Ashoke Khera, Manoj K Jurutka, Peter W Rochel, Natacha Kim, Kyu Kwang Rowswell-Turner, Rachael B Singh, Rakesh K Moore, Richard G |
| description | Small-molecule inhibitors of PD-L1 are postulated to control immune evasion in tumors similar to antibodies that target the PD-L1/PD-1 immune checkpoint axis. However, the identity of targetable PD-L1 inducers is required to develop small-molecule PD-L1 inhibitors. In this study, using chromatin immunoprecipitation (ChIP) assay and siRNA, we demonstrate that vitamin D/VDR regulates PD-L1 expression in acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) cells. We have examined whether a VDR antagonist, MeTC7, can inhibit PD-L1. To ensure that MeTC7 inhibits VDR/PD-L1 without off-target effects, we examined competitive inhibition of VDR by MeTC7, utilizing ligand-dependent dimerization of VDR-RXR, RXR-RXR, and VDR-coactivators in a mammalian 2-hybrid (M2H) assay. MeTC7 inhibits VDR selectively, suppresses PD-L1 expression sparing PD-L2, and inhibits the cell viability, clonogenicity, and xenograft growth of AML cells. MeTC7 blocks AML/mesenchymal stem cells (MSCs) adhesion and increases the efferocytotic efficiency of THP-1 AML cells. Additionally, utilizing a syngeneic colorectal cancer model in which VDR/PD-L1 co-upregulation occurs in vivo under radiation therapy (RT), MeTC7 inhibits PD-L1 and enhances intra-tumoral CD8
T cells expressing lymphoid activation antigen-CD69. Taken together, MeTC7 is a promising small-molecule inhibitor of PD-L1 with clinical potential. |
| doi_str_mv | 10.3390/cancers15133432 |
| format | Article |
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T cells expressing lymphoid activation antigen-CD69. Taken together, MeTC7 is a promising small-molecule inhibitor of PD-L1 with clinical potential.</description><identifier>ISSN: 2072-6694</identifier><identifier>EISSN: 2072-6694</identifier><identifier>DOI: 10.3390/cancers15133432</identifier><identifier>PMID: 37444542</identifier><language>eng</language><publisher>Switzerland: MDPI AG</publisher><subject>Acute myeloid leukemia ; Alfacalcidol ; Antibodies ; Apoptosis ; Bone marrow ; Calcifediol ; CD69 antigen ; CD8 antigen ; Cell activation ; Cell viability ; Chromatin ; Colorectal carcinoma ; Dimerization ; Gene regulation ; Genomics ; Immune checkpoint ; Immunoprecipitation ; Immunotherapy ; Life Sciences ; Lymphocytes T ; Malignancy ; Mesenchymal stem cells ; Monoclonal antibodies ; Myelodysplastic syndrome ; Neutrophils ; Ovaries ; Pancreas ; Pancreatic cancer ; PD-1 protein ; PD-L1 protein ; Radiation therapy ; Retinoid X receptors ; siRNA ; Stem cells ; T cells ; Tumorigenesis ; Tumors ; Viral antibodies ; Vitamin D ; Vitamin D receptors</subject><ispartof>Cancers, 2023-06, Vol.15 (13), p.3432</ispartof><rights>COPYRIGHT 2023 MDPI AG</rights><rights>2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>Distributed under a Creative Commons Attribution 4.0 International License</rights><rights>2023 by the authors. 2023</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c523t-f9a193fbbec80ff44daae0aeac0e3079baf58ca04418453a5f03e532afbee9763</citedby><cites>FETCH-LOGICAL-c523t-f9a193fbbec80ff44daae0aeac0e3079baf58ca04418453a5f03e532afbee9763</cites><orcidid>0000-0002-1434-5670 ; 0000-0001-7421-9767 ; 0000-0002-8225-4025 ; 0000-0002-4950-9161 ; 0000-0003-1911-2064 ; 0000-0001-5574-737X ; 0000-0002-1124-9202 ; 0000-0002-3573-5889 ; 0000-0001-5598-5263 ; 0000-0002-8620-0710</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC10340436/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC10340436/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,881,27901,27902,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/37444542$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttps://hal.science/hal-04274207$$DView record in HAL$$Hfree_for_read</backlink></links><search><creatorcontrib>Khazan, Negar</creatorcontrib><creatorcontrib>Quarato, Emily R</creatorcontrib><creatorcontrib>Singh, Niloy A</creatorcontrib><creatorcontrib>Snyder, Cameron W A</creatorcontrib><creatorcontrib>Moore, Taylor</creatorcontrib><creatorcontrib>Miller, John P</creatorcontrib><creatorcontrib>Yasui, Masato</creatorcontrib><creatorcontrib>Teramoto, Yuki</creatorcontrib><creatorcontrib>Goto, Takuro</creatorcontrib><creatorcontrib>Reshi, Sabeeha</creatorcontrib><creatorcontrib>Hong, Jennifer</creatorcontrib><creatorcontrib>Zhang, Naixin</creatorcontrib><creatorcontrib>Pandey, Diya</creatorcontrib><creatorcontrib>Srivastava, Priyanka</creatorcontrib><creatorcontrib>Morell, Alexandra</creatorcontrib><creatorcontrib>Kawano, Hiroki</creatorcontrib><creatorcontrib>Kawano, Yuko</creatorcontrib><creatorcontrib>Conley, Thomas</creatorcontrib><creatorcontrib>Sahasrabudhe, Deepak M</creatorcontrib><creatorcontrib>Yano, Naohiro</creatorcontrib><creatorcontrib>Miyamoto, Hiroshi</creatorcontrib><creatorcontrib>Aljitawi, Omar</creatorcontrib><creatorcontrib>Liesveld, Jane</creatorcontrib><creatorcontrib>Becker, Michael W</creatorcontrib><creatorcontrib>Calvi, Laura M</creatorcontrib><creatorcontrib>Zhovmer, Alexander S</creatorcontrib><creatorcontrib>Tabdanov, Erdem D</creatorcontrib><creatorcontrib>Dokholyan, Nikolay V</creatorcontrib><creatorcontrib>Linehan, David C</creatorcontrib><creatorcontrib>Hansen, Jeanne N</creatorcontrib><creatorcontrib>Gerber, Scott A</creatorcontrib><creatorcontrib>Sharon, Ashoke</creatorcontrib><creatorcontrib>Khera, Manoj K</creatorcontrib><creatorcontrib>Jurutka, Peter W</creatorcontrib><creatorcontrib>Rochel, Natacha</creatorcontrib><creatorcontrib>Kim, Kyu Kwang</creatorcontrib><creatorcontrib>Rowswell-Turner, Rachael B</creatorcontrib><creatorcontrib>Singh, Rakesh K</creatorcontrib><creatorcontrib>Moore, Richard G</creatorcontrib><title>Vitamin D Receptor Antagonist MeTC7 Inhibits PD-L1</title><title>Cancers</title><addtitle>Cancers (Basel)</addtitle><description>Small-molecule inhibitors of PD-L1 are postulated to control immune evasion in tumors similar to antibodies that target the PD-L1/PD-1 immune checkpoint axis. However, the identity of targetable PD-L1 inducers is required to develop small-molecule PD-L1 inhibitors. In this study, using chromatin immunoprecipitation (ChIP) assay and siRNA, we demonstrate that vitamin D/VDR regulates PD-L1 expression in acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) cells. We have examined whether a VDR antagonist, MeTC7, can inhibit PD-L1. To ensure that MeTC7 inhibits VDR/PD-L1 without off-target effects, we examined competitive inhibition of VDR by MeTC7, utilizing ligand-dependent dimerization of VDR-RXR, RXR-RXR, and VDR-coactivators in a mammalian 2-hybrid (M2H) assay. MeTC7 inhibits VDR selectively, suppresses PD-L1 expression sparing PD-L2, and inhibits the cell viability, clonogenicity, and xenograft growth of AML cells. MeTC7 blocks AML/mesenchymal stem cells (MSCs) adhesion and increases the efferocytotic efficiency of THP-1 AML cells. Additionally, utilizing a syngeneic colorectal cancer model in which VDR/PD-L1 co-upregulation occurs in vivo under radiation therapy (RT), MeTC7 inhibits PD-L1 and enhances intra-tumoral CD8
T cells expressing lymphoid activation antigen-CD69. Taken together, MeTC7 is a promising small-molecule inhibitor of PD-L1 with clinical potential.</description><subject>Acute myeloid leukemia</subject><subject>Alfacalcidol</subject><subject>Antibodies</subject><subject>Apoptosis</subject><subject>Bone marrow</subject><subject>Calcifediol</subject><subject>CD69 antigen</subject><subject>CD8 antigen</subject><subject>Cell activation</subject><subject>Cell viability</subject><subject>Chromatin</subject><subject>Colorectal carcinoma</subject><subject>Dimerization</subject><subject>Gene regulation</subject><subject>Genomics</subject><subject>Immune checkpoint</subject><subject>Immunoprecipitation</subject><subject>Immunotherapy</subject><subject>Life Sciences</subject><subject>Lymphocytes T</subject><subject>Malignancy</subject><subject>Mesenchymal stem cells</subject><subject>Monoclonal antibodies</subject><subject>Myelodysplastic syndrome</subject><subject>Neutrophils</subject><subject>Ovaries</subject><subject>Pancreas</subject><subject>Pancreatic cancer</subject><subject>PD-1 protein</subject><subject>PD-L1 protein</subject><subject>Radiation therapy</subject><subject>Retinoid X receptors</subject><subject>siRNA</subject><subject>Stem cells</subject><subject>T cells</subject><subject>Tumorigenesis</subject><subject>Tumors</subject><subject>Viral antibodies</subject><subject>Vitamin D</subject><subject>Vitamin D 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N</creatorcontrib><creatorcontrib>Gerber, Scott A</creatorcontrib><creatorcontrib>Sharon, Ashoke</creatorcontrib><creatorcontrib>Khera, Manoj K</creatorcontrib><creatorcontrib>Jurutka, Peter W</creatorcontrib><creatorcontrib>Rochel, Natacha</creatorcontrib><creatorcontrib>Kim, Kyu Kwang</creatorcontrib><creatorcontrib>Rowswell-Turner, Rachael B</creatorcontrib><creatorcontrib>Singh, Rakesh K</creatorcontrib><creatorcontrib>Moore, Richard G</creatorcontrib><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Immunology Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>Research Library (Alumni 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Database</collection><collection>ProQuest One Academic Middle East (New)</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Applied & Life Sciences</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>ProQuest Central Basic</collection><collection>MEDLINE - Academic</collection><collection>Hyper Article en Ligne (HAL)</collection><collection>Hyper Article en Ligne (HAL) (Open Access)</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Cancers</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Khazan, Negar</au><au>Quarato, Emily R</au><au>Singh, Niloy A</au><au>Snyder, Cameron W A</au><au>Moore, Taylor</au><au>Miller, John P</au><au>Yasui, Masato</au><au>Teramoto, Yuki</au><au>Goto, Takuro</au><au>Reshi, Sabeeha</au><au>Hong, Jennifer</au><au>Zhang, Naixin</au><au>Pandey, Diya</au><au>Srivastava, Priyanka</au><au>Morell, Alexandra</au><au>Kawano, Hiroki</au><au>Kawano, Yuko</au><au>Conley, Thomas</au><au>Sahasrabudhe, Deepak M</au><au>Yano, Naohiro</au><au>Miyamoto, Hiroshi</au><au>Aljitawi, Omar</au><au>Liesveld, Jane</au><au>Becker, Michael W</au><au>Calvi, Laura M</au><au>Zhovmer, Alexander S</au><au>Tabdanov, Erdem D</au><au>Dokholyan, Nikolay V</au><au>Linehan, David C</au><au>Hansen, Jeanne N</au><au>Gerber, Scott A</au><au>Sharon, Ashoke</au><au>Khera, Manoj K</au><au>Jurutka, Peter W</au><au>Rochel, Natacha</au><au>Kim, Kyu Kwang</au><au>Rowswell-Turner, Rachael B</au><au>Singh, Rakesh K</au><au>Moore, Richard G</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Vitamin D Receptor Antagonist MeTC7 Inhibits PD-L1</atitle><jtitle>Cancers</jtitle><addtitle>Cancers (Basel)</addtitle><date>2023-06-30</date><risdate>2023</risdate><volume>15</volume><issue>13</issue><spage>3432</spage><pages>3432-</pages><issn>2072-6694</issn><eissn>2072-6694</eissn><abstract>Small-molecule inhibitors of PD-L1 are postulated to control immune evasion in tumors similar to antibodies that target the PD-L1/PD-1 immune checkpoint axis. However, the identity of targetable PD-L1 inducers is required to develop small-molecule PD-L1 inhibitors. In this study, using chromatin immunoprecipitation (ChIP) assay and siRNA, we demonstrate that vitamin D/VDR regulates PD-L1 expression in acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) cells. We have examined whether a VDR antagonist, MeTC7, can inhibit PD-L1. To ensure that MeTC7 inhibits VDR/PD-L1 without off-target effects, we examined competitive inhibition of VDR by MeTC7, utilizing ligand-dependent dimerization of VDR-RXR, RXR-RXR, and VDR-coactivators in a mammalian 2-hybrid (M2H) assay. MeTC7 inhibits VDR selectively, suppresses PD-L1 expression sparing PD-L2, and inhibits the cell viability, clonogenicity, and xenograft growth of AML cells. MeTC7 blocks AML/mesenchymal stem cells (MSCs) adhesion and increases the efferocytotic efficiency of THP-1 AML cells. Additionally, utilizing a syngeneic colorectal cancer model in which VDR/PD-L1 co-upregulation occurs in vivo under radiation therapy (RT), MeTC7 inhibits PD-L1 and enhances intra-tumoral CD8
T cells expressing lymphoid activation antigen-CD69. Taken together, MeTC7 is a promising small-molecule inhibitor of PD-L1 with clinical potential.</abstract><cop>Switzerland</cop><pub>MDPI AG</pub><pmid>37444542</pmid><doi>10.3390/cancers15133432</doi><orcidid>https://orcid.org/0000-0002-1434-5670</orcidid><orcidid>https://orcid.org/0000-0001-7421-9767</orcidid><orcidid>https://orcid.org/0000-0002-8225-4025</orcidid><orcidid>https://orcid.org/0000-0002-4950-9161</orcidid><orcidid>https://orcid.org/0000-0003-1911-2064</orcidid><orcidid>https://orcid.org/0000-0001-5574-737X</orcidid><orcidid>https://orcid.org/0000-0002-1124-9202</orcidid><orcidid>https://orcid.org/0000-0002-3573-5889</orcidid><orcidid>https://orcid.org/0000-0001-5598-5263</orcidid><orcidid>https://orcid.org/0000-0002-8620-0710</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 2072-6694 |
| ispartof | Cancers, 2023-06, Vol.15 (13), p.3432 |
| issn | 2072-6694 2072-6694 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_10340436 |
| source | MDPI - Multidisciplinary Digital Publishing Institute; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central; PubMed Central Open Access |
| subjects | Acute myeloid leukemia Alfacalcidol Antibodies Apoptosis Bone marrow Calcifediol CD69 antigen CD8 antigen Cell activation Cell viability Chromatin Colorectal carcinoma Dimerization Gene regulation Genomics Immune checkpoint Immunoprecipitation Immunotherapy Life Sciences Lymphocytes T Malignancy Mesenchymal stem cells Monoclonal antibodies Myelodysplastic syndrome Neutrophils Ovaries Pancreas Pancreatic cancer PD-1 protein PD-L1 protein Radiation therapy Retinoid X receptors siRNA Stem cells T cells Tumorigenesis Tumors Viral antibodies Vitamin D Vitamin D receptors |
| title | Vitamin D Receptor Antagonist MeTC7 Inhibits PD-L1 |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-19T05%3A17%3A26IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Vitamin%20D%20Receptor%20Antagonist%20MeTC7%20Inhibits%20PD-L1&rft.jtitle=Cancers&rft.au=Khazan,%20Negar&rft.date=2023-06-30&rft.volume=15&rft.issue=13&rft.spage=3432&rft.pages=3432-&rft.issn=2072-6694&rft.eissn=2072-6694&rft_id=info:doi/10.3390/cancers15133432&rft_dat=%3Cgale_pubme%3EA757714476%3C/gale_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2836340253&rft_id=info:pmid/37444542&rft_galeid=A757714476&rfr_iscdi=true |